tbuckley/cabot-search huggingface dataset:
Abstract 4064: PD-1 blockade therapy enhances the antitumor effects of lymphodepletion and adoptive T cell transfer
Authors: Satoshi Watanabe, Miho Takahashi, Ryo Suzuki, Masashi Arita, Ko Sato, Toshiya Fujisaki, Aya Ohtsubo, Satoshi Shoji, Kunihiro Shono, Takaaki Masuda, Tomoki Sekiya, Koichiro Nozaki, Tomohiro Tanaka, Rie Kondo, Yu Saida, Satoshi Hokari, Toshiyuki Koya, Toshiaki Kikuchi
Journal: Cancer Research (2023)

Abstract Background: Lymphodepleting cytotoxic regimens, such as chemotherapy and radiotherapy, have shown the ability to enhance antitumor immunity. Although the mechanisms of antitumor effects augmentation in tumor-bearing hosts after lymphodepletion and T cell transfer have been intensively investigated, the influence of lymphodepletion followed by T cell transfer on immune checkpoint molecules (ICMs) expressed on tumor cells and immune cells remains to be elucidated. In the current study, we evaluated the effects of lymphodepletion and adoptive T cell transfer on ICMs in the tumor microenvironment. In addition, we investigated whether lymphodepletion and adoptive transfer of T cells augments antitumor effects of anti-PD-1 blockade therapy. Methods: B6 mice were inoculated subcutaneously with the MCA205 murine fibrosarcoma. On day 7, mice were lymphodepleted by sublethal irradiation with 500 cGy and were reconstituted intravenously with spleen cells from normal mice as a source of naïve T cells. These mice were injected intraperitoneally with anti-PD-1 mAb on days 7 and 14. On day 21, tumor tissues were harvested, and single cell suspensions were labeled with fluorophore-conjugated antibodies for FACS analyses. Results: The expressions of ICMs, including PD-L1, PD-1, TIGIT, TIM-3 and LAG-3, were upregulated on recipient CD4+ and CD8+ T cells in the tumor microenvironment. In contrast, these ICMs were significantly reduced in transferred donor T cells. Administration of anti-PD-1 antibodies after lymphodepletion and adoptive transfer of T cells significantly inhibited tumor progression. Furthermore, transfer of both donor CD4+ and CD8+ T cells was responsible for this augmentation of antitumor effects. Conclusions: Our observations suggest that a possible mechanism of the antitumor effect augmentation mediated by lymphodepletion followed by T cell transfer is the prevention of donor T cell exhaustion and dysfunction. Blockade of PD-1 significantly enhanced the antitumor effects of lymphodepletion and T cell transfer. Citation Format: Satoshi Watanabe, Miho Takahashi, Ryo Suzuki, Masashi Arita, Ko Sato, Toshiya Fujisaki, Aya Ohtsubo, Satoshi Shoji, Kunihiro Shono, Takaaki Masuda, Tomoki Sekiya, Koichiro Nozaki, Tomohiro Tanaka, Rie Kondo, Yu Saida, Satoshi Hokari, Toshiyuki Koya, Toshiaki Kikuchi. PD-1 blockade therapy enhances the antitumor effects of lymphodepletion and adoptive T cell transfer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4064.
Abstract 6104: Prognostic and therapeutic impact of a homologous recombination repair protein TONSL in cancer stem cells
Authors: Hani Lee, SeokGyeong Choi, Sojung Ha, Woo-Young Kim
Journal: Cancer Research (2023)

Abstract Previously, we found that an important homologous recombination repair protein ‘Tonsoku Like, DNA Repair Protein’ (TONSL) might be required for glioblastoma cancer stem cell (CSC). In this study, we further investigated the role of TONSL in CSC from several cancer cell lines from different tissues. We also analyzed the clinical data available from the public databases to find the clinical impact of TONSL. The higher expression of TONSL is associated with the worse prognosis of lung and gastric cancer. Interestingly, in breast cancer, while its higher expression is also the negative prognostic marker of the luminal A and HER2 positive cancers, that is rather the positive prognostic marker for luminal B and basal cancers. TONSL expression is higher in all 4 subtypes of breast cancer, and ovarian cancer than the corresponding normal tissues. The knockdown of TONSL in an ovarian cancer cell line, OVCAR8, results in the increase of G2/M cells and apoptotic cells in the bulk cultured population while increase also the senescence cells only in the CSC population leading to the severe loss of CSC population. TONSL and the close binding partner in homologous recombination repair (HRR), MMS22L, both were essential for the CSC growth but the bulk cultured cells could survive without those two in a colon cancer cell line, HCT15 suggesting the importance of HRR in colon CSC. Indeed, gemcitabine treatment induced DNA breaks showed a synergistic cytotoxicity with those two HRR factors knockdown in the CSC only. These results suggest that the TONSL and MMS2L mediated HRR is essential for the CSC and while most of bulk cultured cancer cells circumvent the HRR deficit. Collectively, these data showed that the CSCs ultimately depend on the HRR process which requires TONSL and, therefore, CSC population may be more vulnerable to HRR targeting therapeutic approaches. Citation Format: Hani Lee, SeokGyeong Choi, Sojung Ha, Woo-Young Kim. Prognostic and therapeutic impact of a homologous recombination repair protein TONSL in cancer stem cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6104.
Abstract 4931: Novel cancer suppressing role of REIC/DKK3 protein through a downregulation of cell surface PD-L1 in breast cancer cells
Authors: Yuma Gohara, Nahoko Tomonobu, Rie Kinoshata, Lena Audebert, Youyi Chen, Ni Luh Gede Yoni Komalasari, Fan Jiang, Chikako Yoshizawa, Hitoshi Murata, Ken-ichi Yamamoto, Masakiyo Sakaguchi
Journal: Cancer Research (2023)

Abstract Adenovirus vector carrying REIC gene (Ad-REIC) is currently in clinical evaluation. The anti-cancer effect of Ad-REIC is mainly caused by two ways, cancer specific apoptosis via endoplasmic reticulum stress with an abundant REIC protein and indirect immune effects by the secreted REIC protein. The former had been well studied that gave us general comprehension of its mechanisms, however latter has still not been fully elucidated. To clear this, we have aimed to identify putative receptor(s) to the extracellularly secreted REIC protein, and have fortunately succeeded to identify five candidates. Surprisingly, the identified receptors all worked to bind with PD-L1 and hold it to stabilize on the plasma membrane, and the REIC binding to the receptors induced liberation of PD-L1 from the receptors’ lock, resulting in an accelerated degradation of PD-L1. This novel insight may lead to the elucidation in important part of the REIC-mediated indirect anti-cancer role. Citation Format: Yuma Gohara, Nahoko Tomonobu, Rie Kinoshata, Lena Audebert, Youyi Chen, Ni Luh Gede Yoni Komalasari, Fan Jiang, Chikako Yoshizawa, Hitoshi Murata, Ken-ichi Yamamoto, Masakiyo Sakaguchi. Novel cancer suppressing role of REIC/DKK3 protein through a downregulation of cell surface PD-L1 in breast cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4931.
Abstract 2700: ORM-6151: A first-in-class CD33-antibody enabled GSPT1 degrader for AML
Authors: James Palacino, Pedro Lee, Hangyeol Jeong, Yeonjoon Kim, Yoojin Song, Uttapol Permpoon, Wesley Wong, Chen Bai, Nathan Fishkin, Khuloud Takouri, Eunjun Yu, Yong Yi, Anna Skaletskaya, Min-Soo Kim, Da-Yeong Kim, Dong-Ki Choi, Peter U. Park
Journal: Cancer Research (2023)

Abstract Targeted protein degraders (TPDs) have expanded the breadth of therapeutic options through both their catalytic mechanism of action and ability to degrade previously “undruggable” target proteins. Prior reports of small-molecule GSPT1 degraders such as CC-90009 in AML demonstrate potent anti-tumor cytotoxicity, but with a potentially narrow therapeutic index. To increase the efficacy vs. tolerability window of TPDs and improve drug delivery, we introduce TPD-Squared (TPD2 TM), a dual-targeted protein degradation approach of combining the catalytic mechanism of targeted protein degradation with the precision of tumor-targeting therapeutic antibodies. We have previously shown in vitro and in vivo efficacy with a HER2-targeted TPD2 conjugate: ORM-5029. Following on that success, we generated conjugates using a CD33-targeting antibody (OR000283) produced by engineering the FAb (H&amp;L) sequences from gemtuzumab onto an IgG1 Fc with N297A variant to inhibit Fc-γR binding. Medicinal chemistry optimization of linker-payloads led to the identification of ORM-6151, which is composed of SMol006, a highly potent GSPT1 degrader conjugated to OR000283 via a novel β-glucuronide releasable linker. ORM-6151 treatment in CD33-expressing cell lines showed picomolar activity with 10-1000-fold greater potency compared to several GSPT1 degrader molecules, including CC-90009 or Mylotarg, and had robust activity in Mylotarg-resistant lines (AML193 and Kasumi6). ORM-6151 also exhibited picomolar potency in in vitro cytotoxicity to primary relapsed/refractory AML patient blasts, with better potency than CC-90009 and Mylotarg. We evaluated ORM-6151 in several in vivo disseminated xenograft models and observed robust efficacy following a single treatment at doses as low as 0.1 mg/kg. Tumor growth inhibition correlated with the degree and duration of GSPT1 depletion and changes in the expression of previously described integrated stress response biomarker genes. In summary, ORM-6151 is a promising, potential therapy for AML and currently in preclinical development as a first-in-class targeted protein degrader therapy with CD33-targeted delivery. Citation Format: James Palacino, Pedro Lee, Hangyeol Jeong, Yeonjoon Kim, Yoojin Song, Uttapol Permpoon, Wesley Wong, Chen Bai, Nathan Fishkin, Khuloud Takouri, Eunjun Yu, Yong Yi, Anna Skaletskaya, Min-Soo Kim, Da-Yeong Kim, Dong-Ki Choi, Peter U. Park. ORM-6151: A first-in-class CD33-antibody enabled GSPT1 degrader for AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2700.
Abstract 5197: NCG-hIL2 mice: a novel model to support the development of T regulatory and NK cells
Authors: Xinxin Zhang, Meirong Wu, Huiyi Wang, Weiwei Yu, Fang Zhu, Jianming Xu, Hongyan Sun, Hongyu Wang, Cunxiang Ju, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao
Journal: Cancer Research (2023)

Abstract Interleukin 2 is a key molecule that promotes the expansion and activation of lymphocytes, including T regulatory cells (Tregs) and natural killer (NK) cells. Tregs are specialized subpopulation of T cells that suppress the immune response by inhibiting T cell proliferation and cytokine production. NK cells are the predominant innate immune subset that mediates anti-tumor and anti-viral responses. Both Tregs and NK cells are two critical immune cells that play an important role in cancer immunotherapy, however, there is a lack of models that supports the in vivo status of these two immune subsets. To address this, we developed a severe immunodeficient mouse model, NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt (NCG-hIL2), by knocking in the human IL-2 gene on the NCG background. The ability of this model to support Treg and NK cells was then compared to NCG and tested with the reconstitution of human peripheral blood mononuclear cells (PBMC) and human hematopoietic stem cells (HSC). In the PBMC engrafted mice, the presence of IL-2 supported the development of T cells, especially the Tregs, with 53.74% in Tregs in NCG-IL2 compared to 4.81% in NCG mice (test at 2 weeks of reconstruction). Similarly, the NK cells are also supported with those cohort engrafted with human HSC (91.63% in NK cells in NCG-IL2 compared to 0.53% in NCG mice, test at 10 weeks of reconstruction). Notably, reconstituted NK cells expressed various NK receptors such as NKp30, NKp44, NKp46, NKG2D, and CD94 in NCG-IL2 mice. They produced comparable levels of granzyme when compared with human peripheral blood-derived NK cells, and a considerable amount of perforin protein was detected in the plasma of huHSC-NCG-hIL2 mice. In conclusion, compared with NCG mice, humanized NCG-hIL2 mice can reconstruct more abundant immune cells and have a wider application in anti-tumor research. It is an ideal model for the preclinical study of anti-tumor therapeutics. Citation Format: Xinxin Zhang, Meirong Wu, Huiyi Wang, Weiwei Yu, Fang Zhu, Jianming Xu, Hongyan Sun, Hongyu Wang, Cunxiang Ju, Santi Suryani Chen, Zhiying Li, Mark Wade Moore, Jing Zhao, Xiang Gao. NCG-hIL2 mice: a novel model to support the development of T regulatory and NK cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5197.
Abstract 4365: Comorbidities at diagnosis are associated with poor outcomes among pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma patients
Authors: Maua Mosha, Jennifer Mayer, Ernest K. Amankwah
Journal: Cancer Research (2023)

Abstract The influence of comorbidities at index diagnosis on outcomes of pediatric leukemia and lymphoma is not well established. We evaluated the association between medical comorbidities and pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) outcomes in a retrospective cohort study using electronic health records from the TriNetX Research Network Database, a global de-identified federated health research network. Study participants included pediatric (≤21 years) patients newly diagnosed with ALL or LL from July 2009-June 2019 and followed through June 2022. The main outcomes included progression/relapse, toxicity, overall mortality and cancer-specific mortality. Comorbidities included chronic lung disease; congenital heart disease; neurologic, immune, hematologic, vascular and genetic disorders; renal disease; gastrointestinal disease; prematurity and hepatobiliary disease. Patients with any comorbidity were matched with patients with no comorbidity on age at diagnosis, gender, race/ethnicity, and treatment using propensity score matching. We identified 5,375 patients diagnosed with ALL/LL with comorbidities and 5,375 without comorbidities after propensity score matching. The mean age at diagnosis was 9.7 years (standard deviation=6.2). A higher proportion of the patients were male (56.9%), White (63.6%) and Not Hispanic or Latino (63.4%). Patients diagnosed with comorbidities had a higher risk for progression/relapse (73% vs 51%; Relative Risk, RR=1.42, 95% confidence interval (CI)=1.38-1.47) and treatment related toxicity (80% vs 50%; RR=1.59, 95% CI=1.54-1.64), compared to patients diagnosed with no comorbidities. Similarly, overall mortality (Hazard ratio, HR=1.62, 95% CI=1.37-1.91) and cancer-specific mortality (HR=4.39, 95% CI=2.28-8.46) were higher among patients diagnosed with comorbidities than those without comorbidities. Comorbidities among patients diagnosed with ALL/LL is associated with poor outcomes independent of treatment and thus targeted interventions for the proper management of these patients are needed to improve outcomes. Citation Format: Maua Mosha, Jennifer Mayer, Ernest K. Amankwah. Comorbidities at diagnosis are associated with poor outcomes among pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4365.
Abstract 5191: Modeling age-related changes in the tumor microenvironment in an orthotopic immunocompetent murine pancreatic cancer model - a novel approach
Authors: Morgan M. Green, Tara Fujimoto, Cullen Taniguchi, Natalie Fowlkes
Journal: Cancer Research (2023)

Abstract Pancreatic cancer is the third leading cause of cancer-related deaths in the U.S. and is most frequently diagnosed between the ages of 65-74 years. Only 11.5% of patients are expected to survive 5 years after diagnosis. There is extensive evidence that tumor microenvironment (TME) plays a critical role in cancer progression and metastasis. Despite the fact that most patients are diagnosed over the age of 60, most preclinical murine tumor models utilize young, healthy, adolescent mice, failing to account for structural and/or functional changes in stroma and immune cells that occur in tissues over time and contribute to tumor progression. Marked differences in lifespan between mice and humans preclude natural development of many age-related physiologic changes in mice that occur in humans over the course of decades. We performed a pilot study to test our hypothesis that KPC pancreatic tumors grown orthotopically in the pancreas of genetically engineered, C57BL/6-Tg (LMNA*G608G) HClns/J mice, a model of Hutchinson-Gilford progeria syndrome with features of accelerated aging, would have altered tumor growth in comparison to tumors in age-matched wild type controls. We found that tumor growth in LMNA mice outpaced that of WT mice. Quantitative digital image analysis showed significantly reduced intratumoral infiltration of CD45+ leukocytes in LMNA mice in comparison to WT (p=0.0098). There was a significant reduction in tumor-infiltrating CD3+ T cells (p=0.038) and F4/80+ macrophages (p=0.0102). Our data supports the hypothesis that functional, age-related, immune and/or stromal changes in the TME impact pancreatic tumor growth and progression. Innovative strategies that better model age-related changes in the TME may better recapitulate the aggressive course of pancreatic cancer in aged patients. Citation Format: Morgan M. Green, Tara Fujimoto, Cullen Taniguchi, Natalie Fowlkes. Modeling age-related changes in the tumor microenvironment in an orthotopic immunocompetent murine pancreatic cancer model - a novel approach. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5191.
Abstract 1134: Therapeutic potential of an antibody-drug conjugate directed against a tumor-specific epitope on podocalyxin
Authors: Pamela M. Austin Dean, Diana Canals Hernaez, Julyanne Brassard, Michael R. Hughes, Erin M. Bell, Kelly M. McNagny, Calvin D. Roskelley
Journal: Cancer Research (2023)

Abstract Podocalyxin (Podxl) is a cell surface sialomucin that is frequently upregulated in tumors with high metastatic potential and its expression is associated with poor outcome in several human cancers. As such, Podxl is emerging as an important prognostic and theragnostic marker. While Podxl is expressed on normal vascular endothelia and kidney podocytes, we sought to produce a novel anti-Podxl antibody that selectively recognizes a tumor-restricted glycoepitope on the extracellular mucin domain of Podxl. The antibody we have produced, PODO447, is specific to the tumor glycoform of Podxl, demonstrated by a lack of binding to normal tissues that are known to express Podxl. In contrast, we show binding of the antibody to tumor cell lines, patient-derived cell lines, and primary tumor tissues. We have previously shown that the majority of tumors in an ovarian carcinoma array (219 cases), including 65% of the high-grade serous histotype, are positive for PODO447. Here, we further show the presence of PODO447 in tumors of the breast, urothelium, pancreas, endometrium, colon, prostate, lung (both small cell and non-small cell), and glioblastoma. To assess the therapeutic potential of our antibody as an antibody drug conjugate (ADC), we coupled PODO447 to the microtubule disruptor monomethyl auristatin E (MMAE) with an enzyme cleavable linker carbamoyl p-aminobenzyl carbamate (PABC), resulting in the ADC PODO447-Vedotin. We demonstrate promising in vitro activity of the ADC to various human tumor cell lines as well as in vivo efficacy to xenografted ovarian and pancreatic tumor lines. Our data reveals PODO447-Vedotin as a tumor-specific and highly efficacious therapeutic agent for the targeting of human tumors and as such, PODO447 exhibits potential for further development as a targeted clinical immunotherapy. Citation Format: Pamela M. Austin Dean, Diana Canals Hernaez, Julyanne Brassard, Michael R. Hughes, Erin M. Bell, Kelly M. McNagny, Calvin D. Roskelley. Therapeutic potential of an antibody-drug conjugate directed against a tumor-specific epitope on podocalyxin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1134.
Abstract 3530: Mechanisms underlying Ewing sarcoma-induced osteolysis
Authors: James J. Williams, Joanna B. Kitlinska
Journal: Cancer Research (2023)

Abstract Ewing Sarcoma (ES) is an aggressive pediatric tumor, which often arises in bones and forms osseous metastases, both of which present as osteolytic lesions. Our previous studies indicated that neuropeptide Y (NPY), which is secreted from ES tumors, stimulates tumor-induced bone degradation via its effect on macrophage recruitment and their subsequent osteoclastic differentiation. This effect was dependent on the autocrine activation of the NPY Y5 receptor (Y5R) expressed by ES cells. However, the exact mechanisms of the osteolytic activity induced by the NPY/Y5R axis remained unknown. To identify the osteolytic factors released from ES cells due to the NPY/Y5R autocrine loop activity, we used shRNA to silence NPY or Y5R in SK-ES-1 ES cells and compared concentrations of known factors involved in the regulation of bone homeostasis in their conditioned media by an antibody array. Four secreted factors were found to be significantly decreased after silencing of NPY signaling: interleukin 8 (IL-8; p&amp;lt;0.005), matrix metalloproteinase 9 (MMP-9; p&amp;lt;0.05), intercellular adhesion molecule 1 (ICAM-1; p&amp;lt;0.005), and monocyte chemoattractant protein 1 (MCP-1; p&amp;lt;0.05). Among these proteins, IL-8 and MMP-9 were selected as the main candidates for mediators of NPY-induced osteolysis. To test their role in ES-mediated stimulation of osteolysis, we co-cultured mouse RAW 264.7 cells, that represent monocyte/macrophage lineage, with SK-ES-1 cells in the presence or absence of the MMP-9 inhibitor (JNJ-0966; 10-7M-10-5M) or anti-IL-8 neutralizing antibody (0.1-0.4µg/ml) and tested their effect on osteoclast differentiation detected by TRAP staining. Inhibiting MMP-9 activity significantly decreased osteoclastogenesis of RAW264.7 cells in dose-dependent manner, while blocking IL-8 had no significant effect on the number of formed osteoclasts. These findings implicate MMP-9 as the mediator of NPY osteolytic activity. Further studies are required to understand the exact mechanisms underlying these effects, as well as potential role of NPY-induced release of MCP-1 in macrophage recruitment to ES tumors. Citation Format: James J. Williams, Joanna B. Kitlinska. Mechanisms underlying Ewing sarcoma-induced osteolysis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3530.